Glycerin derivatives and inhibition of blood PAF

ABSTRACT

Glycerine derivatives of the formula    &lt;IMAGE&gt;  I  wherein the residues R1, R2 and R3 have the significance given in the description, and their hydrates, which inhibit blood platelet activating factor (PAF), are descried.

BRIEF SUMMARY OF THE INVENTION

The glycerine derivatives of the invention are compounds of the formula##STR2## wherein one of the residues R¹, R² and R³ is group U of theformula--OY¹ or --X¹ --C(O)--(A¹)_(n) --Z¹,

another of the residues is group V of the formula --OY² or --X²--C(O)--(A²)_(p) --Z²,

and the remaining residue is group W of the formula --X³ T--(C₂₋₆-alkylene)--N⁺ (Het)Q⁻,

wherein one of X¹, -X² and X³ is oxygen or NH and the other two areoxygen,

Y¹ is C₁₀₋₂₆ -alkyl or C₁₀₋₂₆ -alkenyl,

Y² is C₁₋₆ -alkyl, C₂₋₆ -alkenyl, C₃₋₆ -cycloalkyl, C₅₋₆ -cycloalkenyl,phenyl, benzyl or 2-tetrahydropyranyl,

A¹ and A², independently, are oxygen or NH,

n and p are the integer 1 or 0,

Z¹ is C₉₋₂₅ -alkyl or C₉₋₂₅ -alkenyl,

Z² is C₁₋₅ -alkyl, C₂₋₅ -alkenyl, phenyl or, when (A²)_(p) is notoxygen, Z² is also hydrogen,

T is carbonyl, C(O)O or C(O)NH or, when X³ is oxygen, T is alsomethylene,

--N⁺ (Het) is a 5- to 7-membered aromatic heterocyclic residue,optionally with an additional O-, S- or N-atom, optionally with a fusedbenzene ring and optionally monosubstituted by hydroxy, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, 2-(hydroxy or amino)-ethyl, carbamoyl or ureido, and

Q⁻ is the anion of a strong inorganic or organic acid,

and their hydrates.

DETAILED DESCRIPTION OF THE INVENTION

The glycerine derivatives of the invention are compounds of the formula##STR3## wherein one of the residues R¹, R² and R³ is group U of theformula--OY¹ or --X¹ --C(O)--(A¹)_(n) --Z¹,

another of the residues is group V of the formula --OY² or --X²--C(O)--(A²)_(p) --Z²,

and the remaining residue is group W of the formula --X³ T--(C₂₋₆-alkylene)--N⁺ (Het)Q⁻,

wherein one of X¹, --X² and X³ is oxygen or NH and the other two areoxygen,

Y¹ is C₁₀₋₂₆ -alkyl or C₁₀₋₂₆ -alkenyl,

Y² is C₁₋₆ -alkyl, C₂₋₆ -alkenyl, C₃₋₆ -cycloalkyl, C₅₋₆ -cycloalkenyl,phenyl, benzyl or 2-tetrahydropyranyl,

A¹ and A², independently, are oxygen or NH,

n and p are the integer 1 or 0,

Z¹ is C₉₋₂₅ -alkyl or C₉₋₂₅ -alkenyl,

Z² is C₁₋₅ -alkyl, C₂₋₅ -alkenyl, phenyl or, when (A²)_(p) is notoxygen, Z² is also hydrogen,

T is carbonyl, C(O)O or C(O)NH or, when X³ is oxygen, T is alsomethylene,

--N⁺ (Het) is a 5- to 7-membered aromatic heterocyclic residue,optionally with an additional O-, S- or N-atom, optionally with a fusedbenzene ring and optionally monosubstituted by hydroxy, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, 2-(hydroxy or amino)-ethyl, carbamoyl or ureido, and

Q⁻ is the anion of a strong inorganic or organic acid,

and their hydrates.

The terms "alkyl" and "alkenyl" as used herein relate to straight-chainor branched, saturated or mono-unsaturated residues such as methyl,ethyl, propyl, isopropyl, 2-propenyl, butyl, isobutyl, hexadecyl,heptadecyl, octadecyl and octadecenyl, especially methyl and octadecyl.Examples of C₃₋₆ -cycloalkyl residues Y² are cyclopropyl and cyclohexyl,examples of C₅₋₆ -cycloalkenyl residues Y² are 2-cyclopentenyl andespecially 2-cyclohexenyl. C₂₋₆ -alkylene groups can be straight-chainor branched. Examples thereof are n-butylene, 2-methylpropylene andespecially ethylene and propylene. Examples of heterocyclic residues--N⁺ (Het) are oxazolium, isoxazolium, pyridazinium, quinolinium,isoquinolinium and N-methylimidazolium and, especially, pyridinium andthiazolium.

Examples of anions of strong organic or inorganic acids are C₁₋₄-alkylsulfonyloxy, phenylsulfonyloxy, tosyloxy, camphor-10-sulfonyloxyor Cl⁻, Br⁻, I⁻, ClO₄ ⁻⁻, SO₄ ⁻⁻, PO₄ ⁻⁻⁻ and NO₃ Hu -.

The compounds of formula I can be hydrated. The hydration can take placein the course of the manufacturing process or can occur gradually as aresult of hygroscopic properties of an initially anhydrous compound offormula I.

The compounds of formula I contain at least one asymmetric C-atom andcan, accordingly, exist as optically active enantiomers, asdiastereomers or as mixtures thereof, for example, as racemates.

Preferred compounds of formula I are those in which R³ is W.

More preferred compounds of formula I are those in which R¹ isoctadecylcarbamoyloxy, R² is methoxyformamido, methoxy or especiallymethoxycarbonyloxy and/or in which R³ is 4-(1-pyridiniumchloride)-n-butyryloxy, 4-(1-pyridinium iodide)-n-butyryloxy,4-(3-thiazolium chloride)-n-butyryloxy or especially 4-(3-thiazoliumiodide)-n-butyryloxy.

Examplary of the preferred compounds of the invention are especially

3-[3-[[(R)-2-(methoxycarbonyloxy)-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide, as well as,

3-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide;

1-[3-[[(RS)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride;

1-[3-[[(RS)-2-(1-methoxyformamido)-3-(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]thiazoliumchloride;

1-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumiodide;

1-[3-[[(R)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride; and

3-[3-[[(RS)-2-methoxy-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumchloride.

The compounds of formula I and their hydrates can be prepared by

(a) reacting a compound of the formula ##STR4## wherein the residues R⁴,R⁵ and R⁶ have the same significance as the residues R¹, R² and R³,respectively, but in which a leaving group is present in place of thegroup --N⁺ (Het)Q⁻,

with an amine of the formula N(Het), or

(b) reacting a compound of the formula ##STR5## wherein the residues R⁷,R⁸ and R⁹ have the same significance as the residues R¹, R² and R³,respectively, but in which a hydroxy or an amino group is present inplace of one of the groups U and V,

with an acid of the formula

    Z.sup.1 --(A.sup.1).sub.n --COOH or Z.sup.2 --(A.sup.2).sub.p --COOH IV

or a reactive derivatives thereof, or with an isocyanate of the formula

    Z.sup.1 NCO or Z.sup.2 NCO                                 V

or an imidazolide of the formula ##STR6## wherein Y¹, Y², Z¹, Z², A¹,A², T, N(Het), Q⁻ n and p have the significance given above.

Examples of leaving groups present in the compounds of formula II arechlorine, bromine, iodine, mesyloxy, phenylsulfonyloxy and tosyloxy. Thereaction of a compound II with an amine [N(Het)] can be carried out at atemperature up to the reflux temperature of the reaction mixture,conveniently at about 80° C., optionally in a solvent such asacetonitrile, nitromethane, or an aromatic hydrocarbon, for example,toluene or benzene.

Examples of reactive derivatives of the acids of formula IV are acidbromides or acid chlorides and anhydrides. The reaction of such an acidor of one of its reactive derivatives with a compound of formula III canbe carried out in a known manner. An acid chloride or acid bromide canbe reacted with a compound of formula III in a solvent in the presenceof a base at a temperature of about 0° to 80° C. An anhydride can bereacted with a compound of formula III in the presence of a catalystsuch as dimethylaminopyridine, conveniently in a solvent. Halogenatedhydrocarbons such as chloroform or dichloroethane, can be used assolvents and organic bases such as triethylamine, quinoline or pyridine,or inorganic bases such as alkali or alkaline earth metal hydroxides,carbonates, or bicarbonates, for example, sodium carbonate, potassiumbicarbonate of calcium carbonate, can be used as bases.

The reaction of a compound of formula III with an isocyanate of formulaV or with a corresponding imidazolide of formula VI can be carried outin a solvent such as chloroform, acetone or dimethylformamide at atemperature between about 0° and 100° C., preferably at about 40°-60°C., conveniently in the presence of a catalyst such as a Lewis base, forexample, triethylamine or diisopropylethylamine. If desired, thereaction can also be carried out without the addition of a solvent.

The compounds of formula II can be prepared from the compounds offormula VIII or IX and the compounds of formula III can be prepared fromthe compounds of formula VII according to the following Reaction Scheme:##STR7##

In the compounds of formula VII the residues R¹⁰, R²⁰ and R³⁰ have thesame significance as the residues R¹, R² and R³, except that anoptionally protected hydroxy or amino group or an azido group is presentin place of one of the hydroxy groups U or V.

In the compounds of formula VIII the residues R¹¹, R¹² and R¹³ have thesame significance as the residues R¹, R² and R³, except that anoptionally protected hydroxy or amino group or an azido group is presentin place of the group W.

In the compounds of formula IX one of the residues R¹⁴, R¹⁵ and R¹⁶ isan optionally protected hydroxy or amino group or an azido group,another residue is a group U or V, and the remaining residue is thegroup W in which a leaving group is present in place of --N⁺ (Het)Q⁻.

In the compounds of formula X one of the residues R¹⁷, R¹⁸ and R¹⁹ is anoptionally protected hydroxy or amino grop or an azido group, anotherresidue is an optionally protected hydroxy group, and the remainingresidue is the group U or V.

Examples of protected hydroxy and amino groups are ether groups such asbenzyloxy, trityloxy or 2-tetrahydropyranyloxy, or succinimide,phthalimide, benzyloxycarbonylamino or t-butoxycarbonylamino.

For the preparation of a compound of formula II a compound of formulaVIII in which, for example, R¹³ is hydroxy can be reacted with a halideof the formula Hal--T--(C₂₋₆ -alkylene)--R, wherein R is a leavinggroup, Hal is a halogen atom and T has the above significance, in thepresence of a base such as pyridine or with an isocyanate of the formulaO═C═N--(C₂₋₆ -alkylene)--R.

Alternatively, a compound of formula IX in which, for example, R¹⁴ ishydroxy can be converted into the corresponding compound of formula IIin which R⁴ is the group U or V, which can be carried out in the samemanner as the conversion of a compound III into a compound I describedabove. Analogously, a compound of formula X in which, for example, R¹⁷is hydroxy and R¹⁹ is a protected hydroxy or amino group can beconverted into the corresponding compound of formula VIII in which R¹¹is the group U or V.

An azido group or a protected hydroxy or amino group, for example, R¹³,present in a compound of formula VIII can be converted into the freehydroxy or amino group in a known manner. A benzyl group can be cleavedby hydrogenolysis, for example, over palladium, a trityl group can becleaved by means of trifluoroacetic acid or dilute hydrochloric acid,and a 2-tetrahydropyranyl group can be cleaved by means of dilute acid.An azido group can be converted into the amino group with a complexhydride such as lithium aluminum hydride or by means of hydrogen andpalladium on carbon. Analogously, an azido group or a protected hydroxyor amino group present in a compound of formula VII, IX or X can beconverted into the free hydroxy or amino group. In this manner acompound of formula VII in which, for example, R¹⁰ is a protectedhydroxy or amino group is converted into the corresponding compound offormula III in which R⁷ is hydroxy.

To prepare a compound of formula IX in which, for example, R¹⁶ is thegroup W in which a leaving group is present in place of --N⁺ (Het)Q⁻,the corresponding compound of formula X in which R¹⁹ is hydroxy can betreated in the same manner as described above for the conversion of acompound VIII into a compound of formula II.

The conversion of a compound of formula IX into a compound of formulaVII can be carried out in the same manner as the conversion of acompound II into a compound I.

The compounds of formulas II, III and VII also form part of theinvention.

The compounds of formula I and their hydrates inhibit blood plateletactivating factor (PAF) and can be used in the control or prevention ofillnesses, for example, vascular diseases, such as, thrombosis, heartinfarct and angina pectoris, as well as bronchial asthma caused byallergy, and apoplexy. They are also useful as antiinflammatory andantirheumatic agents.

The inhibition of PAF can be demonstrated as follows:

Platelet-rich plasma (PRP) was and can be prepared by centrifugation ofrabbit blood containing 1/10 volumes of 90 mM trisodium citrate. Theaggregation of the blood platelets was measured with the aid of anaggregometer at 37° C. while stirring. Two (2) minutes after theaddition of the test substance to the PRP, the platelet aggregation wastriggered by a sub-maximum dosage of PAF (4 nM). The IC₅₀ value (in μM)given in the following Table corresponds to that concentration of thetest substance which reduces to a half the aggregation of the bloodplatelets brought about by PAF.

    ______________________________________                                        Product of                                                                    Example:                                                                              1      3      7a   7b   10  11   12   15   16                         ______________________________________                                        IC.sub.50 (μM)                                                                     1.6    3      2    1.6  3   0.6  2    3    1.5                        ______________________________________                                        Product of                                                                    Example:                                                                              20b    21a    21b  21d   21e  21f  24   26                            ______________________________________                                        IC.sub.50 (μM)                                                                     0.25   0.15   0.2  0.2   0.04 0.06 0.15 0.4                           ______________________________________                                    

As mentioned earlier, medicaments containing a compound of formula I ora hydrate thereof also form part of the present invention, as is aprocess for the preparation of such medicaments, which process comprisesbringing one or more compounds of formula I or a hydrate thereof and, ifdesired, one or more other therapeutically valuable substances into agalenical form for administration.

The medicaments can be administered enterally, for example, orally inthe form of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions, or rectally, for example,in the form of suppositories, or as a spray. The administration can,however, also be carried out parenterally, for example, in the form ofsolutions for injection.

For the manufacture of tablets, coated tablets, dragees and hardgelatine capsules, the active substance can be mixed withpharmaceutically inert, inorganic or organic excipients. As suchexcipients for tablets, dragees and hard gelatine capsules, there can beused, for example, lactose, maize starch or derivatives thereof, talc,stearic acid or its salts. For soft gelatine capsules, excipients, suchas, for example, vegetable oils, waxes, fats, semi-solid and liquidpolyols are suitable; depending on the nature of the active substance noexcipients are, however, generally required in the case of soft gelatinecapsules. For the manufacture of solutions and syrups, excipients suchas, for example, water, polyols, saccharose, invert sugar and glucoseare suitable, for injection solutions excipients such as, for example,water, alcohols, polyols, glycerine and vegetable oils are suitable, andfor suppositories, excipients such as, for examle, natural or hardenedoils, waxes, fats and semi-liquid or liquid polyols are suitable.

The pharmaceutical preparations can contain, in addition, preservingagents, solubilizers, stabilizing agents, wetting agents, emulsifyingagents, sweetening agents, coloring agents, flavoring agents, salts forvarying the osmotic pressure, buffers, coating agents or antioxidants.

The dosage of the active substance can vary within wide limits and is,of course, fitted to the individual requirements in each particularcase. In general, in the case of oral administration a dosage of about0.1 to 20 mg/kg, preferably of about 0.5 to 4 mg/kg, per day can beappropriate for adults; however, the upper limit just given can also beexceeded if this should be found to be indicated.

EXAMPLE 1 A. Preparation of the starting material

(a) A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecylglycerine and0.16 ml of triethylamine in 2 ml of chloroform is added dropwise to asolution, cooled to 0° C., of 0.16 ml of 4-chlorobutyryl chloride in 1ml of chloroform. The reaction mixture is stirred at room temperature,diluted with 5 ml of chloroform and washed in succession with 5 ml of 1Nsodium hydroxide and 3×10 ml of water. The organic phase is dried andconcentrated. The residue is chromatographed on silica gel while elutingwith hexane-ether (19:1). There is obtained(R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in the formof an oily residue.

(b) A solution of 0.4 g of(R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 20 ml ofglacial acetic acid is treated with 0.120 g of palladium oxide andhydrogen. The catalyst is removed by filtration under suction and thefiltrate is dried under reduced pressure. There is obtained(R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine of melting point 48° C.

(c) A solution of 0.33 g of(R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 10 ml ofdichloroethane is treated at 80° C. with 10 ml of methyl isocyanate. Thesolution is evaporated and the residue is chromatographed on silica gelwhile eluting with ether. There is obtained(R)-1-O-(4-chlorobutyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerineof melting point 61°-62° C. (dec.).

Preparation of the product

A solution of 0.2 g of(R)-1-O-(4-chloro-butyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerinein 10 ml of pyridine is heated to 80° C. for 16 hours. The solution isevaporated and the residue is treated with toluene by azeotropicdistillation. The residue is recrystallized from ether. There isobtained1-[3-[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]-propyl]pyridiniumchloride of melting point 53°-60° C. (dec.).

EXAMPLE 2 A. Preparation of the starting material

(a) A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecyl glycerine in 25ml of dichloromethane is treated with 0.3 ml of pyridine and cooled to0° C. The solution is treated with 0.2 ml of 2-bromoethyl chloroformate,stirred at room temperature, treated with 10 ml of water and acidifiedto pH 3 with 1N hydrochloric acid. The organic phase is washed withwater, dried and evaporated. The residue is chromatographed on silicagel while eluting with ether/n-hexane (1:1). There is obtained(R)-2-O-benzyl-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine in theform of an oil.

(b) In a manner analogous to Example 1A. (b) from(R)-2-O-benzyl-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine, thereis obtained (R)-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine ofmelting point 64°-65° C. (petroleum ether).

(c) A solution of 0.26 g of(R)-1-[(2-bromo-ethoxy)carbonyl]-3-O-octadecylglycerine in 5 ml ofdichloromethane is treated with a solution of 1 ml of acetic anhydrideand 0.050 g of N,N-dimethylaminopyridine. The reaction mixture istreated with saturated sodium bicarbonate solution and extracted withdichloromethane. The organic phase is washed with water, dried andevaporated. By chromatography on silica gel, while eluting withn-hexane-ether (1:1), there is obtained(R)-2-O-acetyl-1-O-(2-bromoethoxy)-3-O-octadecylglycerine in the form ofan oil.

B. Preparation of the product

A solution of 0.37 g of(R)-2-O-acetyl-1-O-(2-bromoethoxy)-3-O-octadecylglycerine in 10 ml ofpyridine is heated to 80° C. for 3 hours. The solution is evaporated andthe residue is treated with toluene by azeotropic distillation. Theresidue is recrystallized from acetone-ether. There is obtained1-[2-[[[(R)-2-O-acetyl-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridiniumbromide of melting point 55°-60° C. (dec.).

EXAMPLE 3 A. Preparation of the starting material

(a) In a manner analogous to Example 1A. (c),(R)-1-O-octadecyl-3-O-tritylglycerine is converted into(R)-2-O-(methylcarbamoyl)-1-O-octadecyl-3-O-tritylglycerine in the formof an oil.

(b) A solution of 0.57 g of(R)-2-O-(methyl-carbamoyl)-1-O-octadecyl-3-O-tritylglycerine in 15 ml ofdichloromethane is treated with 0.5 ml of trifluoroacetic acid. Thesolution is washed with water and with sodium bicarbonate, dried andevaporated. The residue is recrystallized from dichloromethane-n-hexane.There is obtained (S)-2-O-(methylcarbamoyl)-1-O-octadecylglycerine ofmelting point 68°-69° C.

(c) In a manner analogous to Example 2A. (a),(S)-2-O-(methylcarbamoyl)-1-O-octadecylglycerine is converted into(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-(methylcarbamoyl)-3-O-octadecylglycerineof melting point 62°-65° C.

B. Preparation of the product

A solution of 0.15 g of(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-(methylcarbamoyl)-3-O-octadecylglycerinein 5 ml of pyridine is heated at 60° C. for 20 hours. The solution isevaporated and the residue is treated with toluene by azeotropicdistillation. The residue is recrystallized from acetone. There isobtained1-[2-[[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridiniumbromide of melting point 94° C. (dec.).

EXAMPLE 4

In an manner analogous to Example 3, using thiazole in place ofpyridine, there is obtained3-[2-[[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]thiazoliumbromide of melting point 75° C. (dec.).

EXAMPLE 5 A. Preparation of the starting material

A solution of 0.17 g of (S)-2-O-methyl-1-O-octadecylglycerine in 10 mlof dichloroethane is treated with 1 ml of 2-chloroethyl isocyanate andheated at 80° C. for 25 hours. The solution is evaporated and theresidue is chromatographed on silica gel. After elution withdichloromethane-ether (9:1), there is obtained(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-methyl-3-O-octadecylglycerine inthe form of an oil.

B. Preparation of the product

A solution of 0.035 g of(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-methyl-3-O-octadecylglycerine istreated with 5 ml of pyridine and heated at 80° C. for 3 days. Thesolution is evaporated and the residue is treated with toluene byazeotropic distillation. The residue is recrystallized from acetone.There is obtained1-[2-[1-[(R)-2-methoxy-3-(octadecyloxy)propoxy]formamido]ethyl]pyridiniumchloride of melting point 65° C. (dec.).

EXAMPLE 6 A. Preparation of the starting material

In a manner analogous to Example 2A. (a),(S)-2-O-methyl-1-O-octadecylglycerine is converted into(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-methyl-3-O-octadecylglycerine inthe form of an oil.

B. Manufacture of the product

In a manner analogous to Example 2B.,(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-methyl-3-O-octadecylglycerine isconverted into1-[2-[[[(R)-2-methoxy-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridiniumbromide of melting point 53° C. (dec.).

EXAMPLE 7

In a manner analogous to Example 5 or 6, starting from(RS)-2-O-methyl-1-O-octadecylcarbamoyl-glycerine there is obtained

(a)1-[2-[1-[(RS)-2-methoxy-3-(octadecylcarbamoyloxy)propoxy]formamido]ethyl]pyridiniumchloride, melting point 50°-60° C. (ethyl acetate) or

(b)1-[2-[[[(RS)-2-methoxy-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]oxy]ethyl]pyridiniumbromide, melting point 85°-86° C. (ethyl acetate).

EXAMPLE 8 A. Preparation of the starting material

A solution of 0.3 g of (S)-2-O-(methoxy-carbonyl)-1-O-octadecylglycerinein 15 ml of dichloroethane is treated with 2 ml of 2-chloroethylisocyanate and heated at 80° C. for 24 hours. The solution is evaporatedand the residue is recrystallized from acetone-ether. There is obtained(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O(methoxycarbonyl)-3-O-octadecylglycerineof melting point 77°-78° C.

B. Preparation of the product

A solution of 0.07 g of(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-(methoxycarbonyl)-3-O-octadecylglycerinein 10 ml of pyridine is heated at 80° C. for 3 days. The solution isevaporated and the residue is recrystallized from acetone-n-hexane.There is obtained1-[1-[(R)-2-[(methoxycarbonyl]oxy]-3-(octadecyloxy)propoxy]formamido]-ethyl]pyridiniumchloride of melting point 83° C. (dec.).

EXAMPLE 9

In a manner analogous to Example 8B., using thiazole in place ofpyridine there is obtained3-[2-[1[(R)-2-[methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]formamido]ethyl]thiazoliumchloride of melting point 72° C.

EXAMPLE 10 A. Preparation of the starting material

In a manner analogous to Example 2A. (a), from(S)-2-O-(methoxycarbonyl)-1-O-octadecylglycerine there is obtained(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-(methoxycarbonyl)-3-O-octadecylglycerinein the form of an oil.

B. Preparation of the product

In a manner analogous to Example 6B., from(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-(methoxycarbonyl)-3-O-octadecylglycerine,there is obtained1-[2-[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridiniumbromide of melting point 84°-85° C. (dec.).

EXAMPLE 11

In a manner analogous to Example 10B., from(R)-1-O-[(2-bromoethoxy)carbonyl]-2-O-(methoxycarbonyl)-3-O-(octadecylcarbamoyl)glycerin,there is obtained1-[2-[[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecylcarbamoyl)oxy]propoxy]carbonyl]oxy]ethyl]pyridiniumbromide of melting point 54° C. (dec.). The starting material can beobtained in analogy to Example 10A.

EXAMPLE 12

In a manner analogous to Example 10B., using thiazole in place ofpyridine there is obtained3-[2-[[[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]thiazoliumbromide of melting point 147° C. (dec.).

EXAMPLE 13 A. Preparation of the starting material

(a) In a manner analogous to Example 5A., from(S)-2-O-benzyl-1-O-octadecylglycerine, there is obtained(R)-2-O-benzyl-1-O-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine inthe form of an oil.

(b) In a manner analogous to Example 1A. (b), from(R)-2-O-benzyl-1-O-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine,there is obtained(R)-1-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine of melting point70° C.

(c) In a manner analgous to Example 1A. (c), from(R)-1-[(2-chloroethyl)carbamoyl]-3-O-octadecylglycerine, there isobtained(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-(methylcarbamoyl]-3-O-octadecylglycerineof melting point 91°-92° C.

B. Preparation of the product

In a manner analogous to Example 8B., from(R)-1-O-[(2-chloroethyl)carbamoyl]-2-O-(methylcarbamoyl)-3-O-octadecylglycerine,there is obtained1-[2-[1-[(R)-(2-methylcarbamoyl)-3-(octadecyloxy)propoxy]formamido]ethyl]pyridiniumchloride, MS:M⁺ =550.

EXAMPLE 14 A. Preparation of the starting material

(a) 2 g of sodium azide were added to a solution of 7.75 g of(RS)-1-O-octadecyl-2-O-tosyl-3-O-tritylglycerine in 75 ml of drydimethylformamide. The suspension was stirred at 100° C. for 3 hourswith the exclusion of moisture. After removing the solid material, byfiltration the solvent was removed by distillation and the residue waschromatographed on silica gel with toluene-pyridine (99:1 in vol.).After crystallization from n-hexane, there were obtained 4.05 g of(RS)-1-O-octadecyl-2-deoxy-2-azido3-O-tritylglycerine (63.3% of theory),melting point 58°-59° C.

(b) A solution of 3.6 g of(RS)-1-O-octadecyl-2-deoxy-2-azido-3-O-tritylglycerine in 20 ml of dryether was added drowise with the exclusion of moisture to a suspensionof 130 mg of lithiumaluminumhydride in 50 ml of dry ether. After theevolution of nitrogen had ended, the mixture was stirred at roomtemperature for 10 minutes. Ice cubes were then added and the reactionmixture was stirred for 30 minutes. The ether phase was then separated.The solid phase was washed with ether and the combined ether phases weredried. After removing the solvent, by distillation, the residue waschromatographed on a silica gel column with ether-methanol (9:1 invol.). After crystallization from n-hexane, there were obtained 3.1 g of(RS)-1-O-octadecyl-2-deoxy-2-amino-3-O-tritylglycerine (90.1% oftheory), melting point 56°-57° C.

(c) 5 ml of 25% aqueous hydrochloric acid were added to a solution,heated to 95° C., of 4.65 g of(RS)-1-O-octadecyl-2-deoxy-2-amino-3-O-tritylglycerine in 100 ml ofdioxane and the reaction mixture was held at 95° C. for 30 minutes. Uponcooling, there were obtained 2.75 g (yield: 87.4%) of(RS)-1-O-octadecyl-2-deoxy-2-aminoglycerine hydrochloride, melting point110°-111° C.

(d) 1.4 go of potassium hydroxide in 5 ml of water were added dropwisewhile stirring to a solution of 2.75 g of(RS)-1-O-octadecyl-2-deoxy-2-aminoglycerine hydrochloride in 30 ml ofmethanol. The methanol was then removed by distillation. Ten (10) ml ofwater and 100 ml of dichloromethane were added to the residue. 0.89 g ofmethyl chloroformate were added dropwise to the mixture while stirring.After stirring at room temperature for 11/2 hours, the phases wereseparated in a separating funnel. The organic phase was washed withwater, dried and, after distilling the solvent and the excess reagent,the residue was crystallized from n-hexane. There were obtained 2.90 gof (RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine (100%yield), melting point 63°-64° C.

(e) 0.2 ml of 2-chloroethyl chloroformate (1.4 mmol) in 2 ml ofchloroform was added dropwise with the exclusion of moisture to asolution of 0.4 of(RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine (1 mmol) in 5ml of chloroform and 0.25 ml of pyridine in an ice-bath. The reactionmixture was stirred at room temperature for 2 hours. After working-upthe reaction mixture was filtered over silica gel with ether and theproduct was crystallized from n-hexane. There was obtained 0.475 g of(RS)-1-O-[(2-chloroethoxy)carbonyl]-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerine(93.5% of theory), melting point 58°-59° C.

B. Preparation of the product,1-[2-[[[(RS)-2-(1-methoxyformamido)-3-octadecyloxy]propoxy]oxy]ethyl]pyridiniumchloride

0.3 g of(RS)-1-O-[(2-chloroethoxy)carbonyl]-2-deoxy-2-(1-methoxyformamide)-3-O-octadecylglycerinewas reacted with 5 ml of dry pyridine at 80° C. for 24 hours. Theproduct was chromatographed on silica gel with chloroform-methanol (7:3)and then with chloroform-methanol-water (60:35:5). The product,dissolved in methanol, was then subjected to a percolation through 10 mlof an anion exchanger in the Cl⁻ form. There were obtained 125 mg of abeige compound (36% of theory), melting point 152°-154° C.

EXAMPLE 15 A. Preparation of the starting material

In a manner analogous to Example 14A.e),(RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine was convertedwith 3-chloropropionyl chloride into(RS)-1-O-(3-chloropropionyl)-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerineof melting point 65°-66° C.

B. Preparation of the product

In a manner analgous to Example 14B.,(RS)-1-O-(3-chloropropionyl)-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerinewere converted into1-[2-[[[(RS)-2-(1-methoxyformamido)-3-(octadecyloxy)propoxy]carbonyl]oxy]ethylpyridiniumchloride, melting point 190°-192° C.

EXAMPLE 16

In a manner analogous to Example 15,(RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine was convertedwith 4-chlorobutyryl chloride into(RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)-3-O-(4-chlorobutyryl)glycerine,melting pont 73°-74° C., and the latter was converted into1-[3-[[[(RS)-2-(1-methoxyformamido)-3-(octadecyloxy)propoxy]carbonyl]oxy]propyl]pyridiniumchloride, melting point 200° C. (dec.)

EXAMPLE 17 A. Preparation of the starting material

0.75 g of (RS)-1-O-octadecyl-2-deoxy-2-(1-methoxyformamido)glycerine wasreacted with 1 ml of 2-chloroethyl isocyanate at 100° C. for 2 hourswith the exclusion of moisture. After completion of the reaction theexcess reagent was removed by distillation and the residue wascrystallized from n-hexane. There are obtained 0.88 g (92.8% of theory)of(RS)-1-O-[(2-chloroethyl)carbamoyl]-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerine,melting point 73°-74° C.

B. Preparation of the product

In a manner analogous to Example 14B.,(RS)-1-O-[(2-chloroethyl)carbamoyl]-2-deoxy-2-(1-methoxyformamido)-3-O-octadecylglycerinewas converted into1-[2-[1-[(RS)-2-(1-methoxyformamido)-3-(octadecyloxy)propoxy]formamido]ethyl]pyridiniumchloride, melting point 195°-197° C.

EXAMPLE 18 A. Preparation of the starting material

(a) In a manner analogous to Example 14A. (a),(RS)-1-O-octadecyl-3-O-tosylglycerine was converted into(RS)-1-O-octadecyl-3-deoxy-3-azidoglycerine, melting point 42° C.(n-hexane).

(b) A solution of 5 g of (RS)-1-O-octadecyl-3-deoxy-3-azidoglycerine in75 ml of tetrahydrofuran was hydrogenated with 2.5 g of 10%palladium-carbon under normal pressure and at room temperature. After 3hours the catalyst was removed by filtration, the solvent was removed bydistillation and the product,(RS)-1-O-octadecyl-3-deoxy-3-deoxy-3-aminoglycerine, was crystallizedfrom chloroform-hexane. There were obtained 4.1 g of white crystals(88.2% of theory), melting point 68° C.

(c) 2 ml of an aqueous solution of 0.5 g of potassium hydroxide wereadded to a solution of 1.72 g of(RS)-1-O-octadecyl-3-deoxy-3-aminoglycerine in 20 ml of dichloromethane.While stirring, the two-phase system 0.7 ml of 2-bromoethylchloroformate (corresponding to 1.035 g or 5.52 mmol) was addeddropwise. After stirring at room temperature for 1 hour, the phases wereseparated. The organic phase was washed with water and dried. Thesolvent and the excess reagent were removed by distillation, and theresidue was crystallized from n-hexane. There were obtained 2.1 g (84.8%of theory) of(RS)-1-O-octadecyl-3-deoxy-3-[1-(2-bromo)-ethoxyformamido]glycerine,melting point 72°-74° C.

(d) 0.5 g of (RS)-1-O-octadecyl-3-deoxy-3-[1-(2-bromo)ethoxyformamido]glycerine was reacted with 2 ml of methyl isocyanate inthe presence of 0.05 ml of diisopropylethylamine at 40° C. (reflux) for2 hours. The excess reagent was subsequently removed by distillation andthe residue was crystallized from n-hexane. There was obtained 0.49 g(87.9% of theory) of(RS)-1-O-octadecyl-2-O(methylcarbamoyl)-3-deoxy-3-[1-(2-bromo)ethoxyformamido]glycerine,melting point 91°-92° C.

B. Preparation of the product

2 ml of dry pyridine were added to a solution of 0.3 g of(RS)-1-O-octadecyl-2-O-(methylcarbamoyl)-3-deoxy-3-[1-(2-bromo)ethoxyformamido]glycerinein 1 ml of nitromethane. The mixture was left to react at 80° C. for 24hours. The working-up and purification were carried out in analogy toExample 14B., with the exception that the ion exchanger was present inthe Br⁻ form. There was obtained 0.1 g (26.1% of theory) of1-[2-[[(RS)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propyl]carbamoyl]ethyl]pyridiniumbromide, melting point 195° C. (dec.).

EXAMPLE 19

(a) Analogously to Example 1, there was prepared3-methyl-1-[3-[[(R)-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]propylimidazoliumchloride in the form of a wax, MS:M⁺ =552;

(b) analogously to Example 3 there was prepared1-[2-[[[(S)-[(methylcarbonyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]oxy]ethyl]pyridiniumbromide, m.p. 96° C. (dec.);

(c) analogously to Example 6 there was prepared1-[2-[[[3-methoxy-2(R)-octadecyloxy)propoxy]carbonyl]-oxy]ethyl]pyridiniumbromide, m.p. 47° C. from acetone (dec.);

(d) analogously to Example 5 and 16 there was prepared1-[3-[[(R)-2-(benzyloxy)-3-(octadecyloxy)propoxy]carbonyl]propyl]pyridiniumchloride in the form of a wax; MS:M⁺ =582;

(e) analogously to Example 8 there was prepared1-[2-[1-[(R)-2-[(methoxycarbonyl)oxy]-1-[(octadecyloxy)methyl]ethoxy]formamido]ethyl]pyridiniumchloride, m.p. 57° C.

EXAMPLE 20

Analogously to Example 7b and Example 15 there were prepared

(a)1-[3-[[(RS)-2-methoxy-3-O-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride in the form of a colorless wax, MS:M⁺ =549;

(b)3-[3-[[(RS)-2-methoxy-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumchloride, m.p. 60°-62° C. from ethyl acetate.

EXAMPLE 21

Analogously to Example 11 and Example 16 there were prepared

(a)1-[3-[[(RS)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride, m.p. 51° C.;

(b)1-[3-[[(R)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride, m.p. 55° C.;

(c)1-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride, MS:M⁺ =593;

(d)1-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumiodide, MS:M⁺ =593;

(e)3-[3-[[(R)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide m.p. 64° C. (dec.);

(f)3-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide, m.p. 71° C.

EXAMPLE 22

Analogously to the above Examples there were prepared

(a)1-[4-[2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]butyl]pyridiniumbromide, m.p. 193° C.;

(b)1-[3-[[(RS)-2-[(methylcarbonyl)oxy]-3-(octadecanoyloxy)propoxy]carbonyl]propyl]pyridiniumchloride in the form of a wax, MS:M⁺ =564.

EXAMPLE 23 A. Preparation of the starting material

(a) 15.35 g of (RS)-1-O-benzyl-3-O-tritylglycerine (Helv. Chim. Acta 65,1982, 1059) were dissolved in 75 ml of chloroform. 10 ml of pyridinewere added, followed by 10.5 g of tosyl chloride. After 24 hours at roomtemperature the chloroform was removed by distillation. The residue wastaken up in 50 ml of pyridine, 10 ml of water and then 10 g of potassiumbicarbonate were added. After removing the solvent by distillation, theresidue was taken up in toluene, the solid material was separated, theorganic phase was then shaken out with water, dried and evaporated. Theproduct crystallized from a melt upon cooling. Yield 95%, m.p. 98°-100°C.

(b) Analogously to Example 14A (a) to 14A (d) the(RS)-1O-benzyl-2-O-tosyl-3-O-tritylglycerine obtained was converted insuccession into

(RS)-1-O-benzyl-2-deoxy-2-azido-3-O-tritylglycerine,

(RS)-1-O-benzyl-2-deoxy-2-amino-3-O-tritylglycerine, m.p. 67°-69° C.,

(RS)-1-O-benzyl-2-deoxy-2-aminoglycerine hydrochloride m.p. 148°-149°C., and

(RS)-1-O-benzyl-2-deoxy-2-(1-methoxyformamido)glycerine.

(c) 0.45 g of (RS)-1-O-benzyl-2-deoxy-2-(1-methoxyformamido)glycerinewas treated with 0.6 g of octadecyl isocyanate and the solution washeated to 90° C. for 1 hour. The mixture was chromatographed on silicagel with a mixture of toluene and ethyl acetate (4:1). Aftercrystallization from n-hexane, there was obtained 0.65 g of(RS)-1-O-benzyl-2-deoxy-2-(1-methoxyformamido)-3-O-(octadecylcarbamoyl)glycerine,m.p. 65°-67° C.

(d) 4.9 g of(RS)-1-O-benzyl-2-deoxy-2-(1-methoxyformamido)-3-O-(octadecylcarbamoyl)glycerinedissolved in 75 ml of tetrahydrofuran were hydrogenated in the presenceof 1 g of 10% palladium-carbon under a slight hydrogen excess pressure.4.05 g of(RS)-2-deoxy-2-(1-methoxyformamido)-1-O-octadecylcarbamoylglycerine wereobtained, m.p. 86° C. (from n-hexane).

(e) 0.75 ml of 4-chlorobutyryl chloride in 5 ml of chloroform was addeddropwise with the exclusion of moisture to a solution of 2 g of(RS)-2-deoxy-2-(1-methoxyformamido)-1-O-octadecylcarbamoylglycerine (4.5mmol) in 20 ml of chloroform and 0.7 ml of triethylamine in an ice-bath.The reaction mixture was stirred at room temperature for 2 hours. Afterworking-up, the reaction product was filtered on silica gel withdichloromethane/ether (1:1). 2.3 g of(RS)-1-O-(4-chlorobutyryl)-2-deoxy-2-(1-methoxyformamido)-3-O-(octadecylcarbamoyl)glycerinewere obtained after crystallization from n-hexane, m.p. 68°-70° C.

B. Preparation of the product

Analogously to Example 14B, from 0.4 g of the chloride obtained underA(e) there was obtained 0.2 g of1-[3-[[(RS)-2-(1-methoxyformamido)-3-(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]pyridiniumchloride (44% of theory), m.p. 200° C. (dec.).

EXAMPLE 24

Analogously to Example 23B., there was obtained1-[3-[[(RS)-2-(1-methoxyformamido)-3-(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]thiazoliumchloride, m.p. 180° C. (dec.).

EXAMPLE 25 A. Preparation of the starting material

(a) Analogously to Example 14A (a) and (b),(RS)-1-O-tosyl-3-O-benzylglycerine (Helv. Chim. Acta 65, 1982, 1059) wasconverted via (RS)-1-deoxy-1-azido-3-O-benzylglycerine into

(RS)-1-deoxy-1-amino-3-O-benzylglycerine, m.p. 76°-77° C.

(b) 0.33 g of (RS)-1-deoxy-1-amino-3-O-benzylglycerine was dissolved in20 ml of dichloromethane and treated with 0.8 g of stearoyl chloride.The mixture was stirred in the presence of an aqueous solution ofpotassium hydroxide. The(RS)-1-deoxy-1-octadecanamido-3-O-benzylglycerine obtained from theorganic phase was chromatographed on silica gel with ether. Aftercrystallization from n-hexane, there was obtained 0.5 g of crystals,m.p. 72°-73° C.

(c) 0.45 g of (RS)-1-deoxy-1-octacecanamido-3-O-benzylglycerine wasacetylated with 0.2 g of acetic anhydride and 20 mg of4-dimethylaminopyridine as the catalyst. After working-up, filtration onsilica gel with hexane/ether (1:1) and crystallization in n-hexane,there was obtained 0.49 g of(RS)-1-deoxy-1-octadecanamido-2-O-acetyl-3-O-benzylglycerine, m.p.53°-55° C.

(d) Analogously to Example 23A (d) and (e), this benzyl ether wasconverted via

(RS)-1-deoxy-1-octadecanamido-2-O-acetylglycerine m.p. 66°-68° C. (fromn-hexane), into

(RS)-2-O-acetyl-1-O-(4-chlorobutyryl)-3-deoxy-3-octadecanamidoglycerine,m.p. 55°-56° C.

B. Preparation of the product

Analogously to Example 14B, from 0.3 g of(RS)-2-O-acetyl-1-O-(4-chlorobutyryl)-3-deoxy-3-octadecanamidoglycerine,there was obtained 0.16 g of1-[3-[[(RS)-2-acetoxy-3-octadecanamidopropoxy]carbonyl]propyl]pyridiniumchloride (46% of theory), m.p. 220° C. (dec.).

EXAMPLE 26 A. Preparation of the starting material

(a) A solution of 0.9 g of (RS)-1-deoxy-1-amino-3-O-benzylglycerine in20 ml of dichloromethane was added to an aqueous potassium hydroxidesolution. A solution of 1.7 g of octadecyl chloroformate in 10 ml ofdichloromethane was added dropwise to the mixture while stirring. Afterstirring at room temperature for 1 hour, the mixture was worked-up andthe compound obtained was chromatographed on silica gel withn-hexane/ether (1:1). After crystallization from n-hexane, there wereobtained 1.6 g of crystals, m.p. 58°-59° C.

(b) 2.2 g of(RS)-1-deoxy-1-[1-(octadecyloxy)formamido]-3-O-benzylglycerine wereacylated with methyl chloroformate to give 2.15 g of(RS)-1-deoxy-1-[1-(octadecyloxy)formamido]-2-O-methoxycarbonyl-3-O-benzylglycerine,m.p. 52°-54° C. (from n-hexane).

(c) Analogously to Example 23A (d) and (e), from the resulting benzylether there was obtained via

(RS)-1-deoxy-1-[1-(octadecyloxy)formamido]-2-O-methoxycarbonylglycerine,m.p. 56°-57° C. (from n-hexane),

(RS)-1-deoxy-1-[1-(octadecyloxy)formamido]-2-O-methoxycarbonyl-3-O-(4-chlorobutyryl)glycerine.

B. Preparation of the product

Analogously to Example 14B, 0.4 g of(RS)-1-deoxy-1-[1-(octadecyloxy)formamido]-2-O-methoxycarbonyl-3-O-(4-chlorobutyryl)glycerinewas converted into 0.15 g of1-[3-[[(RS)-2-[(methoxycarbonyl)oxy[-3-[1-(octadecyloxy)-formamido]propoxy]carbonyl]propyl]pyridiniumchloride, (31.8% of theory), m.p. 168° C.

EXAMPLE A

A compound of formula I can be used as follows as the active substancefor the preparation of pharmaceutical preparations:

    ______________________________________                                        (a) Tablets         1 tablet contains                                         ______________________________________                                        Active substance    200 mg                                                    Microcrystalline cellulose                                                                        155 mg                                                    Maize starch         25 mg                                                    Talc                 25 mg                                                    Hydroxypropylmethylcellulose                                                                       20 mg                                                                        425 mg                                                    ______________________________________                                    

The active substance is mixed with half of the microcrystallinecellulose and granulated with a 10 percent solution ofhydroxypropylmethylcellulose in a mixture of isopropanol and methylenechloride. The granulate is dried, sieved and mixed with the remainder ofthe adjuvants. It is then pressed on a press to biplanar tablets of 12mm diameter with a break-bar.

    ______________________________________                                        (b) Capsules    1 capsule contains                                            ______________________________________                                        Active substance                                                                              100.0 mg                                                      Maize starch     20.0 mg                                                      Lactose          95.0 mg                                                      Talc             4.5 mg                                                       Magnesium stearate                                                                             0.5 mg                                                                       220.0 mg                                                      ______________________________________                                    

The active substance is mixed with the adjuvants and sieved. Afterrenewed mixing, the capsule fill mass obtained is filled intointerlocking gelatine capsules of suitable size on a fully automaticcapsule filling machine.

We claim:
 1. A compound of the formula ##STR8## wherein one of theresidues R¹, R² and R³ is group U of the formula --X¹ --C(O)--(A¹)_(n)--Z¹, another of the residues is group V of the formula --X² --C(O)--A²--Z² and the remaining residue is group W of the formula --X³ T--(C₂₋₆-alkylene)--N⁺ (Het)Q⁻ whereby one of --X¹, --X² and --X³ is oxygen orNH and the other two are oxygen, A¹ and A², independently, are oxygen orNH, n is the integer 1 or 0, Z¹ is C₉₋₂₅ -alkyl or C₉₋₂₅ -alkenyl, Z² isC₁₋₅ -alkyl, C₂₋₅ -alkenyl, or phenyl-T is carbonyl, C(O)O or C(O)NH or,when X³ is oxygen, T is also methylene, -N⁺ (Het) is selected from thegroup consisting of oxazolium, isoxazolium, pyridazinium, quinolinium,isoquinolinium, N-methylimidazolium, pyridinium and thiazolium, and --Q⁻is the anion of a strong inorganic or organic acid, or its hydrate.
 2. Acompound in accordance with claim 1, wherein R³ is group W.
 3. Acompound, in accordance with claim 2, wherein R¹ isoctadecylcarbamoyloxy.
 4. A compound, in accordance with claim 3,wherein R² is methoxy or methoxycarbonyloxy.
 5. A compound, inaccordance with claim 4, wherein R³ is 4-(1-pyridiniumchloride)-n-butyryloxy, 4-(1-pyridinium iodide)-n-butyryloxy,4-(3-thiazolium chloride)-n-butyryloxy or 4-(3-thiazoliumiodide)-n-butyryloxy.
 6. A compound, in accordance with claim 5, whereinR¹ is octadecylcarbamoyloxy; R² is methoxycarbonyloxy; and R³ is4-(1-pyridinium chloride)-n-butyryloxy, 4-(1-pyridiniumiodide)-n-butyryloxy, 4-(3-thiazolium chloride)-n-butyryloxy or4-(3-thiazolium iodide)-n-butyryloxy.
 7. A compound, in accordance claim6, wherein R¹ is octadecylcarbamoyloxy, R² is methoxycarbonyloxy and R³is 4-(thiazolium iodide)-n-butyryloxy, that is,3-[3-[[(R)-2-(Methoxycarbonyloxy)-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide.
 8. A compound selected from the group consisting of3-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide,1-[3-[[(RS)-2-[(methoxycarbonyl)oxy[-3-(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]pyridiniumchloride,1-[3[[(RS)-2-(1-methoxyformamido)-3-(octadecylcarbamoyloxy)propoxy]carbonyl]propyl]thiazoliumchloride, 1-[3-[[(S)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxypropoxy]carbonyl]propyl]pyridinium iodide, and1-[3-[[(R)-2-[(methoxycarbonyl)oxy]-3-[(octadecylcarbamoyl)oxypropoxy]carbonyl]propyl]pyridinium chloride.
 9. A compound of theformula ##STR9## wherein one of the residues R¹⁰, R²⁰ and R³⁰ is group Uof the formula --X¹ --C(O)--(A¹)_(n) --Z¹, another of the residues isgroup V of the formula --X² --C(O)--(A²)_(p) --Z², and the remainingresidue is group W of the formula --X³ T--(C₂₋₆ -alkylene)--N⁺ (Het)Q⁻,wherein one of --X¹, --X² and --X³ is oxygen or NH and the other two areoxygen, A¹ and A², independently, are oxygen or NH, n and p are theinteger 1 or 0, Z¹ is C₉₋₂₅ -alkyl or C₉₋₂₅ -alkenyl, Z² is C₁₋₅ -alkyl,C₂₋₅ -alkenyl, or phenyl, T is carbonyl, C(O)O or C(O)NH or, when X³ isoxygen, T is also methylene, --N⁺ (Het) is selected form the groupconsisting of oxazolium, isoxazolium, pyridazinium, quinolinium,isoquolinium, N-methylimidazolium, pyridinium and thiazolium and Q⁻ isthe anion of a strong inorganic or organic acid; provided that an aminogroup or an azido group is present in place of one of the groups U andV.
 10. A pharmaceutical composition for inhibiting blood plateletactivating factor comprising an effective amount of a compound of theformula ##STR10## wherein one of the residues R¹, R² and R³ is group Uof the formula --OY¹ or --X¹ --C(O)--(A¹)_(n) --Z¹,another of theresidues is group V of the formula --OY² or --X² --C(O)--(A²)_(p) --Z²,and the remaining residue is group W of the formula, --X³ T--(C₂₋₆-alkylene)--N⁺ (Het)Q⁻ wherein one of X¹, --X² and X³ is oxygen or NHand the other two are oxygen, Y¹ is C₁₀₋₂₆ -alkyl or C₁₀₋₂₆ -alkenyl, Y²is C₁₋₆ -alkyl, C₂₋₆ -alkenyl, C₃₋₆ -cycloalkyl, C₅₋₆ -cycloalkenyl,phenyl, benzyl or 2-tetrahydropyranyl, A¹ and A², independently, areoxygen or NH, n and p are the integer 1 or 0, Z¹ is C₉₋₂₅ -alkyl orC₉₋₂₅ -alkenyl, Z² is C₁₋₅ -alkyl, C₂₋₅ -alkenyl, phenyl or, when(A²)_(p) is not oxygen, Z² is also hydrogen, T is carbonyl, C(O)O orC(O)NH or, when X³ is oxygen, T is also methylene, --N⁺ (Het) isselected from the group consisting of oxazolium, isoxazolium,pyridazinium, quinolinium, isoquinolinium, N-methylimidazolium,pyridinium and thiazolium, and Q⁻ is the anion of a strong inorganic ororganic acid, provided that when R¹ is a group of the formula --OY¹ or--OY², R² is a group V or OY¹, and X³ is oxygen, then T is C(O)O orC(O)NH,or its hydrate.
 11. A pharmaceutical composition in accordancewith claim 10, wherein R³ is group W.
 12. A pharmaceutical composition,in accordance with claim 11, wherein R¹ is octadecylcarbamoyloxy.
 13. Apharmaceutical composition, in accordance with claim 12, wherein R² ismethoxy or methoxycarbonyloxy.
 14. A pharmaceutical composition, inaccordance with claim 13, wherein R³ is 4-(1-pyridiniumchloride)-n-butyryloxy, 4-(1-pyridinium iodide)-n-butyryloxy,4-(3-thiazolium chloride)-n-butyryloxy or 4-(3-thiazoliumiodide)-n-butyryloxy.
 15. A pharmaceutical composition, in accordancewith claim 14, wherein R¹ is octadecylcarbamoyloxy; R² ismethoxycarbonyloxy; and R³ is 4-(1-pyridinium chloride)-n-butyryloxy,4-(1-pyridinium iodide)-n-butyryloxy, 4-(3-thiazoliumchloride)-n-butyryloxy or 4-(3-thiazolium iodide)-n-butyryloxy.
 16. Apharmaceutical composition, in accordance with claim 15, wherein R¹ isoctadecylcarbamoyloxy, R² is methoxycarbonyloxy and R³ is4-(3-thiazolium iodide)-n-butyryloxy, that is,3-[3-[[(R)-2-(Methoxycarbonyloxy)-3-[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide.
 17. A method of inhibiting blood platelet activating factorwhich comprises administering to a host requiring such treatment aneffective amount of a compound of the formula ##STR11## wherein one ofthe residues R¹, R² and R³ is group U of the formula --OY¹ or --X¹--C(O)--(A¹)_(n) --Z¹,another of the residues is group V of the formula--OY² or --X² --C(O)--(A²)_(p) --Z², and the remaining residue is groupW of the formula, --X³ T--(C₂₋₆ -alkylene)--N⁺ (Het)Q⁻ wherein one ofX¹, --X² and X³ is oxygen or NH and the other two are oxygen, Y¹ isC₁₀₋₂₆ -alkyl or C₁₀₋₂₆ -alkenyl, Y² is C₁₋₆ -alkyl, C₂₋₆ -alkenyl, C₃₋₆-cycloalkyl, C₅₋₆ -cycloalkenyl, phenyl, benzyl or 2-tetrahydropyranyl,A¹ and A², independently, are oxygen or NH, n and p are the integer 1 or0, Z¹ is C₉₋₂₅ -alkyl or C₉₋₂₅ -alkenyl, Z² is C₁₋₅ -alkyl, C₂₋₅-alkenyl, phenyl or, when (A²)_(p) is not oxygen, Z² is also hydrogen, Tis carbonyl, C(O)O or C(O)NH or, when X³ is oxygen, T is also methylene,--N⁺ (Het) is selected from the group consisting of oxazolium,isoxazolium, pyridazinium, quinolinium, isoquinolinium,N-methylimidazolium, pyridinium and thiazolium, and Q⁻ is the anion of astrong inorganic or organic acid, provided that when R¹ is a group ofthe formula --OY¹ or --OY², R² is a group V or OY¹, and X³ is oxygen,then T is C(O)O or C(O)NH,or its hydrate.
 18. A method in accordancewith claim 17, wherein R³ is group W.
 19. A method, in accordance withclaim 18, wherein R¹ is octadecylcarbamoyloxy.
 20. A method, inaccordance with claim 19, wherein R² is methoxy or methoxycarbonyloxy.21. A method, in accordance with claim 20, wherein R³ is 4-(1-pyridiniumchloride)-n-butyryloxy, 4-(1-pyridinium iodide)-n-butyryloxy,4-(3-thiazolium chloride)-n-butyryloxy or 4-(3-thiazoliumiodide)-n-butyryloxy.
 22. A method, in accordance with claim 21, whereinR¹ is octadecylcarbamoyloxy; R² is methoxycarbonyloxy; and R³ is4-(1-pyridinium chloride)-n-butyryloxy, 4-(1-pyridiniumiodide)-n-butyryloxy, 4(3-thiazolium chloride)-n-butyryloxy or4-(thiazolium iodide)-n-butyryloxy.
 23. A method, in accordance withclaim 22, wherein the compound is3-[3-[[(R)-2-(methoxycarbonyloxy)-3[(octadecylcarbamoyl)oxy]propoxy]carbonyl]propyl]thiazoliumiodide.